Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P20366 (substance P)
 21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Studies in the rabbit retina have shown that infusion of exogenous acetylcholine (ACh) into the vitreal chamber leads to an increase in the amount of substance P (SP) immunoreactivity (Goebel and Pourcho, submitted). This increase was determined to be independent of new peptide synthesis, suggesting that the elevated level of SP is the result of ACh inhibition of an SP-degrading protease. This phenomenon has now been confirmed in vitro in both tissue slice and retinal homogenate assays. These studies have shown that ACh decreases the rate of SP hydrolysis in a concentration dependent manner. Recovery of SP hydrolytic activity following ACh inhibition was found to be directly proportional to the amount of acetylcholinesterase (AChE) activity in the membrane fraction. Specific protease inhibitors were used to determine the relative contributions of membrane associated retinal enzymes to SP-hydrolysis. In the presence of 1 mM 1,10-phenanthroline or p-chloromercuribenzenesulfonic acid all SP-hydrolytic activity was abolished, indicating that the enzyme(s) responsible for the degradation of the peptide is a metallopeptidase. The ACh sensitive retinal enzyme was found to be concentrated in the membrane fraction where it accounts for approximately 70% of the SP hydrolytic activity. Although the precise identity of this enzyme remains to be determined, the present evidence indicates that it shares many of the characteristics of the enzyme substance P-degrading endopeptidase (Endo et al. 1988, 1989). Enkephalinase activity was also found, contributing to 28% of the hydrolytic activity in the membrane fraction. However, the activity of this enzyme was insensitive to elevated levels of ACh. After initial cleavage of SP by the primary hydrolytic enzymes, further degradation of the fragments appears to be carried out by membrane associated serine protease(s). The activity exhibited by this class of enzymes was inhibited by DFP treatment and was not sensitive to ACh. Although AChE does not make a major contribution to the hydrolysis of SP, it does participate in peptide degradation via its esterase activity which controls the level of ACh, thereby modulating the primary SP-hydrolytic enzyme.
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PMID:Hydrolysis of substance P in the rabbit retina: II. The role of a membrane-associated acetylcholine-sensitive metalloendopeptidase. An in vitro study. 137 Nov 83

We discovered an enzyme in human platelets that deamidates substance P and other tachykinins. Because an amidated carboxyl terminus is important for biological activity, we purified and characterized this deamidase. The enzyme, released from human platelets by thrombin, was purified to homogeneity by ammonium sulfate precipitation, followed by chromatography on an octyl-Sepharose column and chromatofocusing on PBE 94. The purified enzyme exhibits esterase, peptidase, and deamidase activities. The peptidase activity (with furylacryloyl-Phe-Phe) is optimal at pH 5.0 while the esterase (benzoyl-tyrosine ethyl ester) and deamidase (D-Ala2-Leu5-enkephalinamide) activities are optimal at pH 7.0. With biologically important peptides, the enzyme acts both as a deamidase (substance P, neurokinin A, and eledoisin) and a carboxy-peptidase (with bradykinin, angiotensin I, substance P-free acid, oxytocin-free acid) at neutrality, although the carboxypeptidase action is faster at pH 5.5. Enkephalins, released upon deamidation of enkephalinamides, were not cleaved. Gly9-NH2 of oxytocin was released without deamidation. Peptides with a penultimate Arg residue were not hydrolyzed. Some properties of the deamidase are similar to those reported for cathepsin A. The deamidase is inhibited by diisopropylfluorophosphate, inhibitors of chymotrypsin-type enzymes, and mercury compounds while other inhibitors of catheptic enzymes, trypsin-like enzymes, and metalloproteases were ineffective. In gel filtration, the native enzyme has an Mr = 94,000 while in non-reducing sodium dodecyl sulfate-polyacrylamide gel electrophoresis the Mr = 52,000 indicating it exists as a dimer. After reduction, deamidase dissociates into two chains of Mr = 33,000 and 21,000 as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. [3H]diisopropylfluorophosphate labeled the active site serine in the Mr = 33,000 chain. The first 25 amino acids of both chains were sequenced. They are identical with the sequences of the two chains of lysosomal "protective protein" which, in turn, has sequence similarity to the KEX1 gene product and carboxypeptidase Y of yeast. This protective protein complexes with beta-galactosidase and neuraminidase in lysosomes and is vitally important in maintaining their activity and stability. A defect in this protein is the cause of galactosialidosis, a severe genetic disorder. The ability of physiological stimuli (e.g. thrombin or collagen) to release the deamidase from platelets indicates that it may also be involved in the local metabolism of bioactive peptides.
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PMID:A peptidase in human platelets that deamidates tachykinins. Probable identity with the lysosomal "protective protein". 169 76

Hirschsprung's disease (Megacolon congenitum) is characterized by a sustained contraction of a segment of the large intestine and a consequent enlargement of the preceding gut segment. Morphologically, Hirschsprung's disease is characterized by an absence of neuronal cell bodies in the intramural ganglia of the contracted segment. An additional characteristic finding is the presence of enlarged nerve trunks in the submucosa and in the layer separating the circular and longitudinal muscle layers. These nerve trunks contain abundant acetylcholine esterase (AChE)-positive nerve fibers. The nerve fiber hyperplasia together with an increased amount of acetylcholine as well as AChE activity in the aganglionic segment suggests a cholinergic hyperinnervation. There are other reports claiming an adrenergic hyperinnervation in the aganglionic segment. Recent studies on the peptidergic innervation of the afflicted intestinal segment have demonstrated marked reduction in the density of nerve fibers storing vasoactive intestinal peptide (VIP), substance P (SP), enkephalin and gastrin releasing peptide (GRP). The frequency of nerve fibers storing calcitonin gene-related peptide (CGRP) and galanin seems less affected. Interestingly, nerve fibers storing neuropeptide Y (NPY) are more frequent than normally in the aganglionic segment, the circular muscle being penetrated by numerous NPY-containing nerve fibers. Thus, neuropeptides have turned out to be interesting and promising new markers in the histochemical diagnosis of Hirschsprung's disease. Other possibilities for the histochemical diagnosis includes the immunocytochemical demonstration of general neuronal markers such as neurospecific enolase (NEC), neurofilament and chromogranins. Techniques demonstrating the cholinergic and adrenergic hyperinnervation in the aganglionic intestine such as AChE staining and staining for adrenergic nerves are also of interest for the diagnosis.
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PMID:Neuronal markers in Hirschsprung's disease with special reference to neuropeptides. 208 Feb 35

The purification and kinetic characterization of cholinesterase from blood plasma (pseudocholinesterase; butyrylcholinesterase: EC 3.1.1.8) is described. The hydrolysis of the artificial peptide substrate Lys-Pro-p-nitroanilide served as a model of the second step in degradation of substance P by dipeptidyl peptidase IV. The substrate is hydrolyzed by a gel-electrophoretic homogeneous cholinesterase preparation with a reaction rate of 5.8 mumol/min X mg and a KM value of 0.12 mmol/l. The proteolytic reaction could not be affected with typical cholinesterase inhibitors NaF and dibucain. On the other hand Lys (pNO2-Z)-Pro and a specific suicide substrate (diacylhydroxylamine derivative) inhibit the activity in a manner analogous to dipeptidyl peptidase IV. Though these active site-directed inhibitors also influenced the benzoylcholine hydrolyzing activity of serum cholinesterase, we conclude from the data that dipeptidyl peptidase IV was the true Lys-Pro-p-nitroanilide cleaving activity. Furthermore, the conclusion can also be drawn that hydrolysis of substance P reported by Lockridge 1982 is caused by the contamination that cannot be completely separated from the esterase during the purification method used.
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PMID:Contamination of highly purified human serum cholinesterase by dipeptidyl peptidase IV causing hydrolysis of substance P. 243 Mar 7

Although certain prostaglandins have been found to be inhibitory to nerve-evoked salivary flow, little is known of the effects the leukotrienes on salivary secretion. It was the purpose of this investigation to examine the effects of leukotrienes C4 (LTC4) and D4 (LTD4) on salivary secretion in the rat, using methacholine or substance P to induce basal secretion, and to test whether or not the observed effects of these eicosanoids were receptor-mediated by using the leukotriene receptor blocker FPL-55712. Methacholine (3 x 10(-4) M), or substance P (1 x 10(-6) M) was infused intra-arterially to stimulate secretion and saliva was collected separately from the parotid gland and the submandibular gland of anesthetized rats. LTC4 and LTD4 (each at 1 x 10(-9) to 1 x 10(-6) M) were found to reduce methacholine- and substance P-induced salivary flow in a dose-related manner. Salivary protein concentration and amylase activity were not significantly altered by the leukotrienes; however, arginine-esterase activity, stimulated by substance P, was increased by both leukotrienes. FPL-55712 (1 x 10(-8) M) was shown to reduce the inhibitory effects of LTC4 and LTD4, suggesting the involvement of leukotriene receptors for these agents in their action.
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PMID:The modulatory effects of leukotrienes C4 and D4 on methacholine- and substance P-induced salivary secretion in rats. 245 57

Human serum cleaves two dipeptides from the N-terminus of the neurohormone substance P. It has been suggested that this degrading activity is inherent to serum cholinesterase. We oppose this, because it turned out that highly purified serum cholinesterase contains traces of dipeptidyl peptidase IV, an enzyme known to attack the N-terminus of substance P. The peptidase is incompletely separated from cholinesterase during the procainamide-gel affinity chromatography as the last step of the usual purification procedure. Physostigmine completely inhibits the hydrolysis of butyrylthiocholine by such purified cholinesterase preparations, but not their substance P-degrading activity. Vice versa, epsilon-carbobenzoxy-lysylproline, an inhibitor of dipeptidyl peptidase IV, inhibits the peptidase activity of these preparations more than their esterase activity. After rechromatography on procainamide gel the peptidase is completely separated and the remaining cholinesterase has lost its substance P-degrading activity. We conclude that the N-terminal region of substance P is not degraded by cholinesterase but by the contaminating dipeptidyl peptidase IV, a different serine enzyme.
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PMID:Substance P in human plasma is degraded by dipeptidyl peptidase IV, not by cholinesterase. 258 Sep 48

Cerebral blood vessels, arteries and veins, are invested with a dense plexus of perivascular nerve fibres containing noradrenaline, acetylcholine esterase vasoactive intestinal polypeptide (VIP), substance P and avain pancreatic polypeptide (APP). The majority of the noradrenaline and APP-containing fibres disappear within one week after sympathectomy, while the other nerve fibres remain. Pharmacological studies of feline pial arteries in vitro have shown the presence of alpha 2- and beta 1- adrenoreceptors mediating contraction and dilatation, respectively. Dilatation can also be obtained by acetylcholine activating muscarinic receptors and by VIP and substance P.
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PMID:Vascular autonomic nerves and corresponding receptors in brain vessels. 612 26

Highly purified human serum cholinesterase (EC 3.1.1.8, also known as pseudocholinesterase and butyrylcholinesterase) had peptidase activity toward substance P. Digestion of substance P was monitored by high performance liquid chromatography, which separated three product peptides. The cleavages occurred sequentially. The first peptide to appear as Arg1-Pro2. The Km for this hydrolysis was 0.3 mM; maximum activity was 7.9 nmol min-1 mg-1 of protein, which corresponded to a turnover number of 0.6 min-1. A second cleavage yielded Lys3-Pro4. A third cleavage occurred at the C-terminal, where the amide was removed from Met11 to yield a peptide containing residues 5-11. Both the peptidase and esterase activities of the enzyme were completely inhibited by the anticholinesterase agent, diisopropylfluorophosphate. Substance P inhibited the hydrolysis of benzoylcholine (a good ester substrate) with a KI of 0.17 mM, indicating that substance P interacted with cholinesterase rather than with a trace contaminant. Peptidase and amidase activities for serum cholinesterase are novel activities for this enzyme. It was demonstrated previously that the related enzyme acetylcholinesterase (EC 3.1.1.7) catalyzed the hydrolysis of substance P, but at entirely different cleavage sites from those reported in the present work. Since butyrylcholinesterase is present in brain and muscle, as well as in serum, it may be involved in the physiological regulation of substance P.
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PMID:Substance P hydrolysis by human serum cholinesterase. 617 30

The effects of the undecapeptide, substance P(SP), on the secretion of mucin and proteolytic enzymes from dispersed cells of the rat submandibular gland were studied. The peptide, at a concentration of 1 X 10(-7) M, stimulated the release of 31.9 +/- 3.0% (mean +/- SEM) of intracellular mucin over 40 min, compared with 12.5 +/- 1.5% in untreated controls (p less than 0.01). This effect was duplicated by the homologous peptides, physalaemin, and eledoisin-related peptide. Substance P action was not affected by pre-incubation of cells with phentolamine or propranolol and was therefore independent of adrenergic stimulation. Furthermore, SP did not enhance the intracellular concentrations of cyclic AMP or cyclic GMP, confirming that cyclic nucleotides were not involved in its stimulus-secretion coupling mechanism. The isoproterenol-stimulated secretion of mucin from dispersed cells was reduced to 75.7% of the normal response (p less than 0.01) after a brief exposure to SP. This inhibitory effect was probably mediated by intracellular events rather than by direct effects on cell surface receptors. However, mucin release after treatment with SP followed by norepinephrine (NE) was 161% of that caused by NE alone (p less than 0.01) and may reflect an additive response to the independent stimulation of SP and NE receptors. Substance P and related peptides had no effect on arginine esterase secretion in the experimental model, although a response was elicited by alpha- and beta-adrenergic agonists. It is, therefore, proposed that serous cells of the granular convoluted tubule in the rat submandibular gland lack substance P receptors.
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PMID:Effect of substance P on exocrine secretion by rat submandibular gland cells. 620 29

Highly purified human plasma butyrylcholinesterase was inhibited by reversible inhibitors of esterase activity and modified by active-site-directed irreversible inhibitors of esterases and proteases. Peptidase and esterase activities of inhibited enzyme were simultaneously essayed from rates of hydrolysis of substance P (first cleavage) and butyrylthiocholine respectively. Inhibition parameters values and rates of inactivation of the two activities provide evidence that the peptidasic site is distinct from the esteratic site.
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PMID:[The peptidase site of butyrylcholinesterase is distinct from the esterase site]. 620 83


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